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Cytopenia

Eltrombopag will be initiated at 50 mg/day (Asians 25 mg/day) and dose adjusted up to 150mg/day based response and safety in participants with Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

Eltrombopag will be initiated at 50 mg/day (Asians 25 mg/day) and dose adjusted up to 150mg/day based response and safety

Eltrombopag

Neal S Young, M.D.

Background:

* Myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia, neutropenia, and thrombocytopenia (low red blood cell, white blood cell, and platelet counts). Patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as a risk of progression to acute leukemia. Standard treatments for MDS have significant relapse rates. MDS patients with thrombocytopenia who fail standard therapies require regular, expensive, and inconvenient platelet transfusions, and are at risk for further serious bleeding complications.
* Eltrombopag is a drug designed to mimic the protein thrombopoietin, which causes the body to make more platelets. Eltrombopag has been able to increase platelet counts in healthy volunteers and in patients with chronic ITP (a disease where patients destroy their own platelets very rapidly and thus develop thrombocytopenia), but researchers do not know if the drug can increase platelet counts in patients with MDS.

Objectives:

* To find out whether eltrombopag can improve platelet counts in patients with MDS.
* To determine whether eltrombopag is safe for patients with MDS.

Eligibility:

* Patients 18 years of age and older who have consistently low blood platelet counts related to MDS that has not responded to conventional treatment.
* Platelet count ≤ 30,000/μL or platelet-transfusion-dependence (requiring at least 4 platelet transfusions in the 8 weeks prior to study entry); OR hemoglobin less than 9.0 gr/dL or red cell transfusion-dependence (requiring at least 4 units of PRBCs in the eight weeks prior to study entry) OR ANC≤500

Design:

* Treatment with eltrombopag tablets once per day for 16-20 weeks.
* Participants will be monitored closely throughout the initial treatment, with weekly blood tests and separate evaluations at the National Institutes of Health (NIH) treatment center every 4 weeks. Bone marrow biopsies may be conducted to check for abnormalities in bone marrow.
* If patients show signs of improved platelet counts after 90 days, treatment will continue with additional doses of eltrombopag.
* Patients who discontinue taking eltrombopag will be evaluated at the NIH treatment center 4 weeks after ending treatment, and again 6 months after ending treatment to check for potential side effects.

The myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia, neutropenia, and thrombocytopenia. Patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as a variable risk of progression to acute leukemia. With the exception of stem cell transplant, the standard treatments for MDS are rarely curative, and relapse rates are significant. MDS patients with cytopenias who fail standard therapies require regular blood or platelet transfusions which are expensive and inconvenient, and are at risk for serious bleeding complications.

Thrombopoietin (TPO) is the principal regulator of platelet production by megakaryocytes in the bone marrow. A 2nd generation TPO-agonist, eltrombopag (Promacta ) has been shown to increase platelets in thrombocytopenic patients with chronic immune thrombocytopenic purpura (ITP). Eltrombopag is administered orally, is well-tolerated, and is FDA approved for the treatment of thrombocytopenia in patients with chronic ITP who failed to respond to standard treatment.

Because the management of MDS patients with persistent cytopenias remains unsatisfactory and novel therapeutic approaches are needed, we propose a non-randomized, pilot, phase II study of eltrombopag in low to Int-2 risk MDS subjects with thrombocytopenia and anemia cytopenias who are either untreated or cytopenias that persist despite treatment with standard therapies to assess its utility in these settings.

Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East Asians), which will be adjusted as clinically indicated to the lowest dose that maintains a stable platelet count greater than or equal to 20,000/microL above baseline while maximizing tolerability. Treatment response will be any increase in a cytopenia, in the lineage that fulfilled eligibility criteria for enrollment and will be defined as: (a) platelet count increases to 20,000/microL above baseline at 16 or 20 weeks , or stable platelet counts with transfusion independence for a minimum of 8 weeks in subjects who were previously transfusion dependent; (b) erythroid response for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment compared with the pretreatment transfusion number in the previous 8 weeks; (c) neutrophil response will be defined in those with a pretreatment absolute neutrophil count (ANC) of \< 0.5 times 10(9)/L as at least a 100% increase or an absolute increase \> 0.5 times 10(9)/L. Subjects meeting a response may remain on the extended access until they meet an off study criteria or the study is closed.

Subjects with response at 16 or 20 weeks may be consented for entry into the extended access part of the trial. In the event that a subject is transfused platelets for a count \>10,000/microL without a medical indication during the study period, the subject may continue on study drug and the response assessment may be extended for an additional 4 weeks to week 20, at the discretion of the principal investigator. Subjects with evidence for a clinical response in any lineage at 16 weeks but not yet meeting full primary endpoint response criteria, and who are tolerating investigational treatment, may receive an additional 4 weeks of eltrombopag and be reassessed after 20 weeks. At that time, if they meet primary endpoint response criteria, they will be eligible to enter the extended access part of the study. If they do not meet primary endpoint response criteria, eltrombopag will be discontinued.

Primary objective is to assess the efficacy of eltrombopag in patients with low to Int-2 risk MDS. Safety of eltrombopag in this subject population will be assessed concurrently.

Secondary objectives include the toxicity profile of extended treatment with eltrombopag (treatment longer than 4 months), reduction in incidence and severity of bleeding episodes, and response following extended access to study drug (treatment longer than 4 months).

The primary endpoint will be the portion of drug responders as defined by changes in the platelet count and/or platelet transfusion requirements, or the proportion of subjects who meet erythroid response, or neutrophil response criteria.. Platelet response is defined as platelet count increases to 20,000/microL above baseline at 16 or 20 weeks, or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined in those with a pretreatment absolute neutrophil count (ANC) of \<0.5 times 10(9)/L as at least a 100% increase or an absolute increase \> 0.5 times 10(9)/L. Subjects with an erythroid, and/or neutrophil response at 16 weeks may continue study medication (extended access) until they meet an off study criteria. Subjects with erythroid, or neutrophil response at 16 weeks may continue study medication for an additional 4 weeks (to ensure eligibility) prior to being consented for entry into the extended access part of the trial. Patients may remain on the extended access until they met an off study criteria.

The toxicity profile will be measured using the CTCAE Version 4.0 criteria.

Secondary endpoints will include incidence of grade 2 or higher bleeding events as measured by CTCAE v. 4.0; changes in serum thrombopoietin level, measured at 4 months; and progression to higher risk MDS as measured by IWG criteria.

A Pilot Study of a Thrombopoietin-Receptor Agonist, Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

A Pilot Study of a Thrombopoietin-Receptor Agonist (TPO-R Agonist), Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

The primary endpoint was hematologic response at 16 or 20 weeks, defined as either: (1) an increase in platelet counts =20.000/uL or transfusion independence for a minimum of 8 weeks; (2) hemoglobin (Hb) increase of =1.5g/dL from baseline, or a reduction in red blood cells (RBC) transfusion of at least 50%; or (3) an increase in absolute neutrophil counts (ANC) of =0.5x109/L or by at least 100% in patients with a baseline ANC \<0.5x109/L.

Changes in serum thrombopoietin level at 16 or 20 weeks

Number of participants with progression to higher risk Myelodysplastic syndrome (MDS) as measured by International Working Group (IWG) 2006 criteria in participants With Low to Int-2 Risk Myelodysplastic Syndrome (MDS) following Eltrombopag.

Progression of disease per modified IWG criteria 2006 were considered: if patients with baseline bone marrow blasts of \< 5% increase by ≥ 50% to \>5% blasts; and either at least 50% decrease in granulocytes or platelets from maximum response, decreasing in Hb by 2g/dL or transfusion dependence. The acquisition of new cytogenetic abnormality without meeting other IWG criteria for progression was not considered disease progression.

Number of participants who achieved a robust response and discontinued Eltrombopag in extended access

A robust response is defined as: as platelets \>50,000/μL, hemoglobin \> 10 g/dL in the absence of transfusions, and neutrophils \> 1,000 for more than 8 weeks.

Number of Participants with Grade 2 or Higher Bleeding Events defined by Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0.

The NCI CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline. Grade 1 Mild is asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 is moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL)\*. Grade 3 is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL\*\*. Grade 4 if life-threatening consequences; urgent intervention indicated. Grade 5 is death related to AE.

National Heart, Lung, and Blood Institute (NHLBI)

Any observed or volunteered adverse events that are as listed in the Eltrombopag Package Insert and/or Investigator's Brochure will not be reported unless (1) the adverse event was not present at baseline exam; (2) the adverse event is previously unknown (not on the label); (3) the adverse event is more severe than on the label; (4) the frequency of the adverse events increases above the listed frequency; or (5) meets the criteria for a serious adverse event.

Eltrombopag (EPAG), a thrombopoietin receptor agonist, was started at 50 mg/day, up to a maximal dose of 150 mg/day, increasing the dose by 25mg every 2 weeks.

Eltrombopag in Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

Eltrombopag in Low to Int-2 Risk Myelodysplastic Syndromes (MDS)

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Low Risk Myelodysplastic Syndromes (MDS) are defined as having a low risk or a score of zero by the International Prognostic Scoring System (IPSS). A zero score is defined as: bone marrow blasts less than 5%, a good karyotype, and 1 of the following cytopenia: Hemoglobin \< 10g/dL, Absolute neutrophil count \< 1800/uL, Platelet count \< 100,000/uL.

IPSS score may range from zero which is the lowest score and is associated with better survival to a high score which is 3.5 and is associated with poorer survival when treatment is not provided.

Low Risk Myelodysplastic Syndromes (MDS)

Intermediate-1 Risk Myelodysplastic Syndromes are defined as having low risk with score from 0.5 to 1 by the International Prognostic Scoring System (IPSS). A 0.5 to 1 score is defined as: bone marrow blasts 5 to 10%, intermediate to poor karyotype and 2 or 3 of the following: Hemoglobin \< 10g/dL, Absolute neutrophil count \< 1800/uL, Platelet count \< 100,000/uL.

IPSS score may range from zero which is the lowest score and is associated with better survival to a high score which is 3.5 and is associated with poorer survival when treatment is not provided.

Intermediate-1 Risk Myelodysplastic Syndromes (MDS)

Intermediate-2 Risk Myelodysplastic Syndromes are defined as having a higher risk with score from 1.5 to 2 by the International Prognostic Scoring System (IPSS). A score of 1.5 to 2 is defined as: bone marrow blasts 11 to 30%, poor karyotype, and 2 or 3 of the following: Hemoglobin \< 10g/dL, Absolute neutrophil count \< 1800/uL, Platelet count \< 100,000/uL.

IPSS score may range from zero which is the lowest score and is associated with better survival to a high score which is 3.5 and is associated with poorer survival when treatment is not provided.

Intermediate-2 Risk Myelodysplastic Syndromes (MDS)

The first five participants enrolled were entered when eligibility criteria included only thrombocytopenia. They were not included in the efficacy analysis set, as requested by the Institutional Review Board, but were included for secondary endpoint and sensitivity analyses.

Bhavisha Patel, MD

Eltrombopag in Low to Int-1 Risk Myelodysplastic Syndrome (MDS)

The first 5 subjects enrolled were not counted toward the accrual target due to changes in protocol.

Number of Participants With Response Between Weeks 16 and 20

Changes in Serum Thrombopoietin Level

Number of Participants With Progression to Higher Risk Myelodysplastic Syndrome as Measured by International Working Group Criteria

Analysis included those participants that participated in extended access portion of study

Number of Participants Who Achieved a Robust Response and Discontinued Eltrombopag

Number of Participants With Grade 2 or Higher Bleeding Events Defined by Common Terminology Criteria for Adverse Events v. 4.0

Initial Treatment (Weeks 1 - 20)

Extended Access: Week 20 to Up to Year 5

Skin and Connective Tissue Diseases

Breast Neoplasms

Neoplasm Metastasis

Breast Diseases

Skin Diseases

Female age 18 and above with negative breast biopsy

Females age 18 and above with any subtype of breast cancer (ductal, lobular, or other)

Females age 18 and above with any subtype of breast cancer (HER2+, ER/PR, TNBC, BRCA1 +/-, other).

Females age 18 and above with any subtype of breast cancer, including metastases

10-12mL of blood will be drawn one time, unless a redraw is needed, in which case up to 24 mL will be drawn (10-12 mL each draw)

Blood draw

Clinical Trials Referral Office

Leandra Pake

Clinical Trials

Scott H. Okuno, M.D.

Determining if Megakaryocytes and Platelets are Harmful or Helpful in Breast Cancer Cell Metastasis

The purpose of this study is to determine how megakaryocytes (cells in the bone marrow responsible for making platelets, which are necessary for blood clotting) affect the survival and growth/division patterns of breast cancer stem cells, and the effects of breast cancer cells on megakaryocyte survival and function. Through chart review, the study team will look at the relationship between different blood components and different breast cancer diagnoses.

Blood draw. 10-12 mL total into lavender-top (EDTA) tubes, however up to 24 mL may be obtained should a redraw be needed.

A Study of Effect of Megakaryocytes and Platelets in Breast Cancer

Megakaryocytes and Platelets, Harmful or Helpful in Breast Cancer Cell Metastasis

Measure of the number of platelets in the blood, reported as platelets per microliter of blood.

Measures the average size of red blood cells, reported as femtoliters (fl).

Ratio between the neutrophil and lymphocyte counts measured in peripheral blood.

Number of tumor educated platelets, measured by the analysis of cell surface markers for expression of certain markers such as VEGF, PDGFR, MMP1, TGFb, and or other cell adhesion molecules.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Pilot Study of a Thrombopoietin-Receptor Agonist, Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)	NCT00961064	Myelodysplastic... Thrombocytopeni...	Eltrombopag	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
A Study of Effect of Megakaryocytes and Platelets in Breast Cancer	NCT06011824	Breast Cancer	Blood draw	18 Years -	Mayo Clinic
A Study of Effect of Megakaryocytes and Platelets in Breast Cancer	NCT06011824	Breast Cancer	Blood draw	18 Years -	Mayo Clinic
A Pilot Study of a Thrombopoietin-Receptor Agonist, Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)	NCT00961064	Myelodysplastic... Thrombocytopeni...	Eltrombopag	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for megakaryocytes